Schizophrenia is a chronic and debilitating disorder that impacts nearly 1% of the world's population. The burden on the families and caregivers of patients is immense, with the cost of care in the United States being greater than $60 billion annually. The exorbitant financial strain of schizophrenia arises, in large part, to a lack of innovation that has resulted in very limited, ineffective and poorly-tolerated treatment options. Virtually all of the antipsychotics approved by the FDA in the past fifty years act exclusively on dopamine and/or serotonin receptor function; however, unfortunately, these antipsychotics are routinely associated with poor patient compliance due to inadequate efficacy and the emergence of serious side effects including motor impairments and metabolic / cardiovascular side effects. The overall goal of this Phase II SBIR is to continue the development of our novel and innovative antipsychotic medications that are proposed to be an effective and safer alternative to the current standards of care. Specifically, cystine-glutamate exchange (system xc-) appears to be altered in schizophrenic patients, and we have shown previously in our Phase I SBIR that targeting this mechanism is highly effective in a rodent model of schizophrenia. This current grant application is designed to capitalize on these findings and our Phase I SBIR funds that were employed to discover and investigate a novel series of molecules engineered to target system xc-. Our lead small molecules are potent drivers of system xc- in cortical cultures in vitro and we have confirmed preclinical proof-of-efficacy in rodent models of schizophrenia. We propose to expand on these findings and further characterize our lead molecule in IND-directed safety pharmacology and toxicology studies, with an eye towards developing a novel therapeutic approach for the treatment of schizophrenia and potentially other psychiatric disorders. PUBLIC HEALTH RELEVANCE: Schizophrenia is a chronic, debilitating disorder that results in a devastating burden on the families and caregivers of patients. The cost of care in the United States is in excess of $60 billion a year. The high costs arise, in part, due to a lack of innovatin that has resulted in very limited treatment options that are routinely associated with poor compliance due to poor efficacy and the emergence of serious side effects. The goal of this Phase II SBIR project is to fully characterize lead drug development candidates identified in work funded by the Phase I grant with an eye towards the development of novel and innovative antipsychotic agents.